The research in this proposal focuses on the development of methods for the preparation of medicinally important heterocyclic ring systems and carbocyclic ring systems. The methodology utilizes the coupling of two very simple and highly accessible partners, highly conjugated acetylenes and transition metal carbene complexes, as the key elements for the design of new processes. New, efficient, and highly flexible synthetic route to a variety of target molecules utilizing these newly developed reactions have been proposed. Specific Aims 1-4 involve the tandem generation of isobenzofurans and/or pyrones and their subsequent cycloaddition reactions. Reliable protocols will be developed for the use of these reactions for the synthesis of ten-membered rings, partially hydrogenated phenanthrene ring systems, isoquinoline ring systems, and benzo-fused flve-membered ring heterocycles. These newly developed reaction processes will subsequently be used as cornerstones for incredibly short synthetic routes to the steroids, morphine alkaloids, hydrophenanthrene antibiotics, benzophenanthridine anti-cancer agents, and indole-containing phosphodiesterase inhibitors. The multicomponent nature of these couplings allows for a high degree of molecular diversity, a tremendous asset for long-term evaluation of structure-activity relationships of pharmaceutical analogs. Specific Aim 5 involves development of a novel synthetic route to the 1-aminopyrrole ring system based on the coupling of enyne-imines with carbene complexes. This reaction will serve as the cornerstone for the synthesis of unsymmetrical dipyrroles and a complementary method for the synthesis of partially hydrogenated phenanthrenes. This methodology will subsequently be employed in a short synthetic route to tanshinones, important components of then herb Dan Shen, and which display a diverse spectrum of biological activity. Specific Aim 6 involves extension of the above processes to the analogous epoxide or aziridine derivatives, and development of protocols for rapid assembly of the medicinally important 3-benzoxepine and 3-benzazepine ring systems.